These reintroduction experiments into established cancer cell lines, which harbor multiple mutations, chromosomal alterations, and epigenetic changes, do not necessarily reflect the loss of function of pVHL in normal cells in the kidney at the beginning of tumor formation, meaning that at early stages of tumor development, pVHL loss may indeed lead to increased DNA damage (16) but that this defect becomes less pronounced as tumor evolution progresses and other mutations contribute to ongoing DNA damage or defects in DNA repair, irrespective of pVHL function. This evidence concerns the gene VHL and cancer.